{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T12:29:06Z","timestamp":1779366546275,"version":"3.53.0"},"reference-count":34,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2023,6,20]]},"abstract":"<jats:sec sec-type=\"background\" xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              The ketone body 3\u2010hydroxybutyrate (3\u2010OHB) increases cardiac output (CO) in patients with heart failure through unknown mechanisms. 3\u2010OHB activates the hydroxycarboxylic acid receptor 2 (HCA\n              <jats:sub>2<\/jats:sub>\n              ), which increases prostaglandins and suppresses circulating free fatty acids. We investigated whether the cardiovascular effects of 3\u2010OHB involved HCA\n              <jats:sub>2<\/jats:sub>\n              activation and if the potent HCA\n              <jats:sub>2<\/jats:sub>\n              \u2010stimulator niacin may increase CO.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Twelve patients with heart failure with reduced ejection fraction were included in a randomized crossover study and examined by right heart catheterization, echocardiography, and blood sampling on 2 separate days. On study day 1, patients received aspirin to block the HCA\n              <jats:sub>2<\/jats:sub>\n              downstream cyclooxygenase enzyme, followed by 3\u2010OHB and placebo infusions in random order. We compared the results with those of a previous study in which patients received no aspirin. On study day 2, patients received niacin and placebo. The primary end point was CO. 3\u2010OHB increased CO (2.3\u2009L\/min,\n              <jats:italic>P<\/jats:italic>\n              &lt;0.01), stroke volume (19\u2009mL,\n              <jats:italic>P<\/jats:italic>\n              &lt;0.01), heart rate (10 bpm,\n              <jats:italic>P<\/jats:italic>\n              &lt;0.01), and mixed venous saturation (5%,\n              <jats:italic>P<\/jats:italic>\n              &lt;0.01) with preceding aspirin. 3\u2010OHB did not change prostaglandin levels, neither in the ketone\/placebo group receiving aspirin nor the previous study cohort. Aspirin did not block 3\u2010OHB\u2010induced changes in CO (\n              <jats:italic>P<\/jats:italic>\n              =0.43). 3\u2010OHB decreased free fatty acids by 58% (\n              <jats:italic>P<\/jats:italic>\n              =0.01). Niacin increased prostaglandin D\n              <jats:sub>2<\/jats:sub>\n              levels by 330% (\n              <jats:italic>P<\/jats:italic>\n              &lt;0.02) and reduced free fatty acids by 75% (\n              <jats:italic>P<\/jats:italic>\n              &lt;0.01) but did not affect CO.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              The acute increase in CO during 3\u2010OHB infusion was not modified by aspirin, and niacin had no hemodynamic effects. These findings show that HCA\n              <jats:sub>2<\/jats:sub>\n              receptor\u2010mediated effects were not involved in the hemodynamic response to 3\u2010OHB.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Registration<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              URL:\n              <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.clinicaltrials.gov\">https:\/\/www.clinicaltrials.gov<\/jats:ext-link>\n              ; Unique identifier: NCT04703361.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.123.029849","type":"journal-article","created":{"date-parts":[[2023,6,11]],"date-time":"2023-06-11T02:28:25Z","timestamp":1686450505000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":22,"title":["Stimulation of the Hydroxycarboxylic Acid Receptor 2 With the Ketone Body 3\u2010Hydroxybutyrate and Niacin in Patients With Chronic Heart Failure: Hemodynamic and Metabolic Effects"],"prefix":"10.1161","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-6363-7406","authenticated-orcid":false,"given":"Nigopan","family":"Gopalasingam","sequence":"first","affiliation":[{"name":"Department of Cardiology Aarhus University Hospital Aarhus N Denmark"},{"name":"Department of Clinical Medicine Aarhus University Aarhus N Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristian Hylleberg","family":"Christensen","sequence":"additional","affiliation":[{"name":"Department of Cardiology Aarhus University Hospital Aarhus N Denmark"},{"name":"Department of Clinical Medicine Aarhus University Aarhus N Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5110-0656","authenticated-orcid":false,"given":"Kristoffer","family":"Berg Hansen","sequence":"additional","affiliation":[{"name":"Department of Cardiology Aarhus University Hospital Aarhus N Denmark"},{"name":"Department of Clinical Medicine Aarhus University Aarhus N Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9228-3869","authenticated-orcid":false,"given":"Roni","family":"Nielsen","sequence":"additional","affiliation":[{"name":"Department of Cardiology Aarhus University Hospital Aarhus N Denmark"},{"name":"Department of Clinical Medicine Aarhus University Aarhus N Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2548-7025","authenticated-orcid":false,"given":"Mogens","family":"Johannsen","sequence":"additional","affiliation":[{"name":"Department of Forensic Medicine Aarhus University Aarhus N Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0144-1305","authenticated-orcid":false,"given":"Lars Christian","family":"Gormsen","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine Aarhus University Aarhus N Denmark"},{"name":"Department of Nuclear Medicine and PET Aarhus University Hospital Aarhus N Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5078-9279","authenticated-orcid":false,"given":"Ebbe","family":"Boedtkjer","sequence":"additional","affiliation":[{"name":"Department of Biomedicine Aarhus University Aarhus N Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0580-373X","authenticated-orcid":false,"given":"Rikke","family":"N\u00f8rregaard","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine Aarhus University Aarhus N Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5627-7322","authenticated-orcid":false,"given":"Niels","family":"M\u00f8ller","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine Aarhus University Aarhus N Denmark"},{"name":"Department of Endocrinology and Metabolism Aarhus University Aarhus N Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik","family":"Wiggers","sequence":"additional","affiliation":[{"name":"Department of Cardiology Aarhus University Hospital Aarhus N Denmark"},{"name":"Department of Clinical Medicine Aarhus University Aarhus N Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.nutr.26.061505.111258"},{"key":"e_1_3_1_3_2","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgaa370"},{"key":"e_1_3_1_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.116.005066"},{"key":"e_1_3_1_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.118.036459"},{"key":"e_1_3_1_6_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.124079"},{"key":"e_1_3_1_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.115.017545"},{"key":"e_1_3_1_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.115.017355"},{"key":"e_1_3_1_9_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00332.2003"},{"key":"e_1_3_1_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abc8861"},{"key":"e_1_3_1_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2020.154452"},{"key":"e_1_3_1_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvz045"},{"key":"e_1_3_1_13_2","first-page":"143","article-title":"Ketoacids? Good medicine?","volume":"114","author":"Cahill GFJ","year":"2003","unstructured":"Cahill GFJ, Veech RL. Ketoacids? Good medicine? Trans Am Clin Climatol Assoc. 2003;114:143\u2013149.","journal-title":"Trans Am Clin Climatol Assoc"},{"key":"e_1_3_1_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2020.165739"},{"key":"e_1_3_1_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.12.022"},{"key":"e_1_3_1_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2016.11.007"},{"key":"e_1_3_1_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-385952-5.00005-1"},{"key":"e_1_3_1_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2012.06.003"},{"key":"e_1_3_1_19_2","doi-asserted-by":"publisher","DOI":"10.2147\/CPAA.S47895"},{"key":"e_1_3_1_20_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3003877"},{"key":"e_1_3_1_21_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C500213200"},{"key":"e_1_3_1_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2012.10.030"},{"key":"e_1_3_1_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9149(86)90846-5"},{"key":"e_1_3_1_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-8703(97)70105-4"},{"key":"e_1_3_1_25_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI23626"},{"key":"e_1_3_1_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4944"},{"key":"e_1_3_1_27_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.48.113006.094746"},{"key":"e_1_3_1_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/0090-6980(89)90088-9"},{"key":"e_1_3_1_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/0090-6980(79)90055-8"},{"key":"e_1_3_1_30_2","first-page":"114","article-title":"Dissociation of the effects of nicotinic acid on vasodilatation and lipolysis by a prostaglandin synthesis inhibitor, indomethacin, in man","volume":"57","author":"Kaijser L","year":"1979","unstructured":"Kaijser L, Eklund B, Olsson AG, Carlson LA. Dissociation of the effects of nicotinic acid on vasodilatation and lipolysis by a prostaglandin synthesis inhibitor, indomethacin, in man. Med Biol. 1979;57:114\u2013117.","journal-title":"Med Biol"},{"key":"e_1_3_1_31_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00420712"},{"key":"e_1_3_1_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardfail.2006.06.005"},{"key":"e_1_3_1_33_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI106082"},{"key":"e_1_3_1_34_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.113.000187"},{"key":"e_1_3_1_35_2","doi-asserted-by":"publisher","DOI":"10.1177\/0271678X15610787"}],"container-title":["Journal of the American Heart Association"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/JAHA.123.029849","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T12:44:58Z","timestamp":1715604298000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/JAHA.123.029849"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,20]]},"references-count":34,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2023,6,20]]}},"alternative-id":["10.1161\/JAHA.123.029849"],"URL":"https:\/\/doi.org\/10.1161\/jaha.123.029849","relation":{},"ISSN":["2047-9980"],"issn-type":[{"value":"2047-9980","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,20]]},"assertion":[{"value":"2023-02-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-05-17","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-06-10","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e029849"}}